ABSTRACT Leptomeningeal collateral circulation and remodeling has recently emerged as a powerful therapeutic target for neurorestorative therapy following stroke. Cerebral vascular occlusion prevents adequate blood flow to neural tissue regions resulting in neuronal cell loss and severe sensorimotor deficits. Retrograde reperfusion occurring in patients with a sufficient collateral response, either prior to or following recanalization, can help stabilize cerebral blood flow (CBF) and aide in penumbral tissue protection. However, the cellular and molecular mechanism(s) underlying this differential patient response in the collateral niche remains unclear. Evidence suggests that endothelial cells (ECs) lining the collateral vessel wall actively respond to changes in blood flow following obstruction and help orchestrate the collateral remodeling process. Our novel pre-clinical findings demonstrate, cell-to-cell contact proteins called Eph receptor tyrosine kinases (EphR), and their membrane bound ephrin ligand(s), are present on cerebral collateral ECs and play a central role in limiting their response in the murine brain following stroke. The research objectives outlined in this application focus on the novel growth suppressive mechanism(s) of EphR signaling on collateral remodeling and neural functional recovery. EC- specific deletion of EphR results in significant neuroprotection and restoration of CBF which reflects a monumental change in collateral growth and production of pro-arteriogenic factors. We hypothesize that activation of EphR signaling mediates acute neural tissue damage and dysfunction by suppressing the EC response during collateral remodeling after stroke. To test this, we will employ cell-specific inducible knockout and bone marrow chimeric mice. We will also investigate the relevance and mechanism(s) of injury-induced collateral remodeling in neural recovery using loss- and reverse-of-function mini-osmotic infusion approaches. These studies will reveal a novel mechanism suppressing the collateral response to stroke and provide therapeutic support for targeting this pathway for the treatment and management of ischemic stroke.